tbuckley/cabot-search huggingface dataset:
Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression
Authors: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster
Journal: Cancer Research (2023)

Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.
Abstract 1667: Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor models
Authors: Fabian Fadi Pusch, Heathcliff Dorado García, Robin Xu, Dennis Guergen, Yi Bei, Lotte Brueckner, Claudia Roeefzaad, Jennifer von Stebut, Victor Bardinet, María del Rocío Chamorro Gonzalez, Angelika Eggert, Johannes H. Schulte, Patrick Hundsdoerfer, Georg Seifert, Kerstin Haase, Beat Schaefer, Marco Wachtel, Anja A. Kühl, Michael Ortiz, Antje M. Wengner, Monika Scheer, Anton G. Henssen
Journal: Cancer Research (2023)

Abstract Elimusertib is a small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR) currently being tested in clinical trials. Despite the known anti-tumor activity in various cancer entities, its effect on many pediatric malignancies remains unknown. We assessed the preclinical activity of elimusertib in a cohort of over 40 cell lines and 30 patient-derived xenograft (PDX) models derived from pediatric solid tumors. Elimusertib reduced tumor growth in all PDX models, with 50% of them achieving stable disease, partial or total response, even in those derived from relapsed tumors. Moreover, elimusertib outperformed the effect of standard of care chemotherapy, particularly in alveolar rhabdomysarcoma. Molecular characterization of the models provide information on response biomarkers with diagnostic potential. In summary, elimusertib shows strong preclinical anti-tumor activity in pediatric solid tumor models, that may translate to clinically meaningful responses in patients. Citation Format: Fabian Fadi Pusch, Heathcliff Dorado García, Robin Xu, Dennis Guergen, Yi Bei, Lotte Brueckner, Claudia Roeefzaad, Jennifer von Stebut, Victor Bardinet, María del Rocío Chamorro Gonzalez, Angelika Eggert, Johannes H. Schulte, Patrick Hundsdoerfer, Georg Seifert, Kerstin Haase, Beat Schaefer, Marco Wachtel, Anja A. Kühl, Michael Ortiz, Antje M. Wengner, Monika Scheer, Anton G. Henssen. Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1667.
Abstract 4454: Loss of CX3CL1 expression mediates immune evasion in <i>STK11</i> mutated lung adenocarcinomas
Authors: Eria Eksioglu, Gabriela M. Wright, Trent R. Percy, Kenneth L. Wright, W. Douglas Cress
Journal: Cancer Research (2023)

Abstract Immunotherapy has improved survival for many cancer patients, especially for immunogenic malignancies such as lung cancer. However, even in lung cancer, the response rate for anti-PD1 therapy (for example) does not exceed 20%. Thus, it is critical to identify mechanisms that block the response to immune checkpoint therapies. STK11 (also known as LKB1) is encoded by the serine threonine kinase 11 gene (STK11). Patients harboring tumors with STK11 mutations have reduced infiltrates of cytotoxic T-cells and clinical studies have shown that they respond poorly to anti-PD1 or anti-PDL-1 therapies regardless of PDL-1 status, which otherwise predicts benefit. Herein, we have used gene expression data from a cohort of 442 lung adenocarcinoma patients to identify CX3CL1 (fractalkine) as a gene silenced in STK11 mutant tumors with potential to be a key direct modulator of the immune system relevant to STK11 loss. To further explore this hypothesis, we have edited the STK11 gene in A549 cells back to wild type (STK11 corrected). As predicted, restoration of STK11 function resulted in modest expression of CX3CL1 as measured by Western blotting. Unexpectedly, exposure of STK11 corrected cells to human immune cells isolated from the blood of healthy donors resulted in a 5 to 10-fold increase in CX3CL1 suggesting interactive signaling between tumor and immune cells. Using transwell assays and STK11 corrected A549 cells we find that restoration of functional STK11 increases immune cell migration, adhesion and invasion in vitro. Finally, cytotoxicity assays demonstrate that STK11 corrected A549 cells are 3 to 5-fold more sensitive to immune cell killing. Taken together these results suggest the hypothesis that CX3CL1 loss mediates immune evasion in STK11 mutant lung adenocarcinomas. Future work will further explore the mechanisms underlying this pathway in preclinical models. Citation Format: Eria Eksioglu, Gabriela M. Wright, Trent R. Percy, Kenneth L. Wright, W. Douglas Cress. Loss of CX3CL1 expression mediates immune evasion in STK11 mutated lung adenocarcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4454.
Abstract 2106: Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease
Authors: Kanve Nagaraj Suvilesh
Journal: Cancer Research (2023)

Abstract Introduction: Non-small cell lung cancer (NSCLC) is by far the leading cancer killer. Identifying personalized treatment strategies to prevent and treat metastases remains an unmet clinical need. Alveolar epithelial type II (AT2) cells are self-renewing epithelial stem cells that have been identified to initiate a majority NSCLCs. Previously, we have reported the presence of multiple AT2 cell types in micrometastatic circulating tumor cell-derived xenograft (CDX) models and patient metastatic tumors. These findings provide a rationale to further study whether and how AT2 cells contribute to metastatic progression. Hypothesis: We hypothesize that AT2 cell types have a functional role in metastasis tumorigenicity of NSCLC. Methods: A library of NSCLC patient-derived circulating tumor cell (CTC) lines, xenograft (PDX) models, and publicly available data sets of patients’ NSCLC tumor tissues were subjected to single cell/bulk RNA sequencing and analysis to determine the frequencies and expression patterns of AT2 subclones. Using magnetic bead sorting AT2 cells were enriched and AT2-associated tumorigenicity, migratory and invasion capacity determined using 3D culture and PDX models. The effects of AT2 depletion on PDX tumor characteristics were evaluated histologically. Frequencies of AT2 phenotypes in primary and metastatic tumors were validated in human tissue microarrays and patient CTCs. Results: An additional AT2 population was identified in NSCLC brain metastases and primary lung tumors that had metastasized already. However, this additional AT2 cell population was absent in primary lung tumors of patients that had not metastasized and in patients with lymph node, pleural and liver metastases. AT2-depleted NSCLC cell lines had reduced tumorigenicity in PDX models in comparison to tumors derived from whole cell populations. In addition, tumors derived from AT2 depleted cell lines were highly necrotic. AT2-depleted cell lines showed decreased migratory and invasion capacity in 3D models. Further, AT2 phenotypes were identified at high rates in NSCLC patients’ metastases and CTCs. Conclusion: Findings indicate an important role of AT2 cells in metastatic progression, beyond their known role in NSCLC initiation. The role of AT2 in metastasis migration, invasion and growth offers unique opportunities to identify novel therapeutic targets. Expansion of translational findings on AT2 cells has high potential for clinical impact to prevent or treat metastatic disease in NSCLC patients. Citation Format: Kanve Nagaraj Suvilesh. Importance of alveolar epithelial cell type 2 populations in non-small cell lung cancer progression from localized to metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2106.
Abstract 4425: GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy
Authors: Remon van Geel, Floris van Delft
Journal: Cancer Research (2023)

Abstract Engagement of T cell or NK cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-IL-15 immunocytokines, based on a variety of molecular architectures, are currently finding their way to the clinic with promising results. Here we demonstrate how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan, can be applied for attachment of IL-15 without prior antibody engineering. Moreover, the immunostimulatory activity of these GlycoConnect™ immune cell engagers (GC™-ICEs) can be modulated by tailoring linker design and payload stoichiometry. In particular, we demonstrate how a protease-cleavable mAb-IL-15 conjugate can be used to prevent systemic activation of the immune system, leading to a significantly improved therapeutic index in rodent models. In vitro and in vivo studies will be presented to showcase the biological activity of these GC™-ICEs in comparison to conventional immunocytokines obtained via genetic engineering. Citation Format: Remon van Geel, Floris van Delft. GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4425.
Abstract 5304: Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature
Authors: Rongzhang Dou, Ehsan Irajizad, Yining Cai, Johannes F. Fahrmann, Jody V. Vykoukal, Yihui Chen, Hiroyuki Katayama, Ali H. Abdel Sater, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Edwin J. Ostrin, Jaffer Ajani, Samir M. Hanash
Journal: Cancer Research (2023)

Abstract Background: Gastric cancer is frequently diagnosed at an advanced stage and is associated with poor outcomes. Harnessing the immune response to tumor antigens which occurs early during tumor development has potential for the early detection of gastric cancer. Methods: Plasma samples from gastric cancer patients were collected before and after treatment and from healthy controls for identification of immunoglobin (Ig)-bound antigens using mass spectrometry. Ingenuity pathway analysis(IPA) was utilized to investigate networks and pathways associated with Ig bound proteins identified in plasmas from cases. A combined biomarker panel was established based on a logistic-regression model and ROC analysis was used to assess panel performance. Results: A total of 65 Ig bound proteins were identified that were upregulated in gastric cancer patients’ plasma compared with healthy control. Canonical pathways involving these immunogenic proteins included HIF-1α, VEGF, actin cytoskeleton, and immunogenic cell death signaling which play important roles in both gastric cancer development and progression. Four of the top ten performing proteins exhibited high mRNA levels in gastric cancer tissue. The association of these four Ig bound proteins in gastric cancer plasmas was further validated using as controls a cohort of MEN1 patients plasmas. A blood-biomarker panel based on these four biomarkers was established using a logistic-regression model which yielded an area under the curve (AUC) of 0.963 (95% confidential interval [CI] =0.89-1.00) for gastric cancer discrimination with a sensitivity of 0.889 at 95% specificity. Conclusion: Our data reveal a panel of plasma Ig-bound antigens associated with the development of gastric cancer with potential application for early detection and monitoring. Citation Format: Rongzhang Dou, Ehsan Irajizad, Yining Cai, Johannes F. Fahrmann, Jody V. Vykoukal, Yihui Chen, Hiroyuki Katayama, Ali H. Abdel Sater, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Edwin J. Ostrin, Jaffer Ajani, Samir M. Hanash. Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5304.
Trifluridine/tipiracil (FTD/TPI) in extensively pre-treated metastatic colorectal cancer (mCRC) patients: Evaluation of prognostic subgroups of the TALLISUR study.
Authors: Meinolf Karthaus, Lena Weiss, Jorge Riera-Knorrenschild, Albrecht Kretzschmar, Manfred Welslau, Ursula Vehling-Kaiser, Henning Pelz, Thomas Jens Ettrich, Swantje Held, Linde Kehrmann, Juergen Hess, Timo Reislaender, Volker Heinemann
Journal: Journal of Clinical Oncology (2023)

3556 Background: Compared to placebo, FTD/TPI significantly improved overall survival (OS) in patients (pts) with pre-treated mCRC in the pivotal phase III RECOURSE trial. Subgroup analyses indicated that all subgroups benefitted from FTD/TPI. Of note, FTD/TPI prolonged survival even more in pts ≥ 65 years old. To evaluate these observations with data from daily clinical practice, we performed a subgroup analysis of the TALLISUR study. Methods: In this prospective, multi-center, German, open-label, phase IV study, pts with extensively pre-treated mCRC chose between best supportive care (BSC) or oral FTD/TPI (35 mg/m 2 bid on days 1 – 5 and 8 – 12 of each 28-day cycle). Duration of treatment and OS were analyzed for various subgroups. Based on a post-hoc analysis of the RECOURSE trial, 3 subgroups were defined according to: best, good and poor prognostic characteristics (BPC, GPC, PPC). Pts with &lt; 3 metastatic sites at inclusion and ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC pts without liver metastasis at inclusion were considered to have BPC. All remaining pts were considered to have PPC. Results: Of 195 eligible pts, 186 pts chose treatment with FTD/TPI, while 9 pts decided to receive BSC only. Median OS was 6.9 (95% CI 6.1 – 8.3) months. Mean duration of treatment with FTD/TPI was 14.6 (range 0.1 – 102.7) weeks. Results of the subgroup analysis are summarized in the table. Pts ≥ 65 years old presented a longer median OS (7.2 vs 6.2 months). Conclusions: When given the choice between treatment and BSC in late-stage CRC, the vast majority of pts opted for treatment. Low metastatic burden and indolent disease were factors of good prognosis for FTD/TPI therapy regarding OS. Independent of baseline characteristics such as age, sidedness, and time of onset of metastases, virtually all pts benefitted from therapy with FTD/TPI. Albeit not statistically significant, elderly pts tend to have improved survival with FTD/TPI, consistent with results from RECOURSE. Clinical trial registration number: EudraCT No 2017-000292-83 . [Table: see text]
Abstract 6630: Flow cytometry immunophenotyping using commercial antibodies to maximize detection of PD-1 in immuno-oncology (I-O) clinical studies with anti-PD-1 check point inhibitors
Authors: Venkat Mohanram, Ming Yang, Angelina Bisconte, Deborah Phippard
Journal: Cancer Research (2023)

Abstract Precision for Medicine’s translational biomarker expertise supports global clinical trials with flow cytometry. A biomarker strategy which includes flow cytometry to generate pharmacokinetic/pharmacodynamic (PK/PD) models for rational design of dose escalation and expansion of clinical studies, may need to consider concomitant drugs for checkpoint inhibition like Pembrolizumab. Precision has optimized the use of commercial anti-PD-1 and anti-IgG4 reagents to detect both free PD-1 and/or Pembro-bound PD-1 when patients are on study with a new molecular entity as either a monotherapy or in combination with concomitant checkpoint inhibitors. For I-O studies conventional efficacy endpoints combined with flow biomarker driven surrogate endpoints enhance therapeutic decisions for determining mechanism of action and biological response when incorporated in early-phase clinical studies. Precision developed and qualified a flow immunophenotyping assay to quantify PD-1 on CD4+ and CD8+ T cells using a commercial PD-1 clone (PD1.3.1.3) and an anti-IgG4. This enabled detection of both free and drug bound PD-1 receptor. We compared detection of PD-1 in PHA stimulated healthy donors treated with saturating Pembrolizumab or no drug treatment. There was not a significant difference observed in PD-1 quantification in the presence or absence of Pembrolizumab, which demonstrated that our approach was able to accurately measure total PD-1 whether free or bound. As Pembrolizumab was titrated from the saturating concentration there was a dose-dependent decrease in detection of PD-1. We have used this assay to detect PD-1 with several new I-O therapies that combined standard anti-PD-1 checkpoint inhibitors, and in these clinical studies for advanced and rare solid tumor indications, we observed an average of 20-40% increase in PD-1 compared to no drug treatment. Immuno-oncology clinical trials which incorporate checkpoint inhibitors like either PD-1 or PD-L1, the availability of commercial reagents are key considerations to detect these receptors when designing a sensitive, selective, and accurate biomarker assay. Citation Format: Venkat Mohanram, Ming Yang, Angelina Bisconte, Deborah Phippard. Flow cytometry immunophenotyping using commercial antibodies to maximize detection of PD-1 in immuno-oncology (I-O) clinical studies with anti-PD-1 check point inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6630.
Abstract 1849: Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2
Authors: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel
Journal: Cancer Research (2023)

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the oxidation of L-Tryptophan (TRP) leading to the formation of immunosuppressive kynurenine (KYN) pathway metabolites. According to TCGA, a substantial fraction of different tumor types expresses both IDO1 and TDO2. In 82 tumor samples (GBM, hepatocellular carcinoma, NSCLC, and ovarian cancer) analyzed for IDO1/TDO2 RNA expression (RNA sequencing) and TRP metabolite content (LC-MS/MS), we found TDO2 highly expressed in hepatocellular carcinoma and to lower levels in NSCLC and ovarian cancer. IDO1 was found to be expressed in NSCLC and ovarian cancer but at higher levels and its expression was correlating with KYN levels. Immunosuppressive properties of KYN and downstream metabolites are mediated through T cell apoptosis and regulatory T cell (Treg) induction. In our hands, KYN at concentrations ≥ 50uM was shown to be immunosuppressive, notably inducing T cell apoptosis. According to our and published data, such high KYN concentrations (≥ 50uM) can be found in a subset of human tumors. As outlined, both IDO1 and TDO2 can contribute to high KYN levels in tumors. Hence, dual IDO1/TDO2 inhibition should be superior in decreasing tumor KYN levels and levering immunosuppression as compared to IDO1 selective inhibition. In this regard, we have generated potent dual IDO1/TDO2 inhibitors inhibiting IDO1 and TDO2 enzyme activity in cellular assays in vitro. To prove the concept of superiority in vivo, we established a dual IDO1/TDO2 expressing human tumor model (LOVO+IFNg) in the mouse and showed that the oral administration of a dual IDO1/TDO2 inhibitor as compared to an IDO1 selective inhibitor showed enhanced KYN/TRP modulation in the tumor. Lead compounds with favorable drug-like properties are currently investigated for pre-clinical development. Citation Format: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel. Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1849.